COPD is a major health problem and is the fourth most common cause of death in the developed countries. COPD represent a spectrum of obstructive airway diseases, including chronic bronchitis and pulmonary emphysema. Besides significant extrapulmonary effects that may contribute to the severity in individual patients, the pulmonary component of COPD is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. Physiological abnormalities in COPD can e.g. include mucuous hypersection and ciliary dysfunction, hyperinflation and gas exchange abnormalities. The abnormal permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destruction of the alveolar wall and without obvious fibrosis is defined as pulmonary emphysema. Regarding the therapy of COPD, no drug has demonstrated effectiveness in halting the decline of lung function so far.
Drug therapy is rather directed to maintain control of symptoms and prevent exacerbation and there is a need for new therapeutic alternatives.
Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease of unknown aetiology associated with a progressive deterioration in lung function and a fatal prognosis despite aggressive therapeutic attempts. IPF is characterized by aberrant proliferation of fibroblasts and deposition of extracellular matrix components leading to the progressive loss in lung function and respiratory failure. An imbalance between the synthesis and degradation of extracellular matrix molecules seems to be involved in the pathogenesis of IPF. At present there is no cure for IPF and the community is still in search of an optimal treatment for IPF.
Uridine nucleotides, the phosphate esters of uridine, had previously been proposed for the treatment of chronic obstructive pulmonary disease and cystic fibrosis, which is a hereditary form of fibrosis. Promotion of mucociliary clearance by uridine triphosphate (UTP) was suggested in WO 99/32085 in view of a treatment of cystic fibrosis. WO 99/09998 was directed to a method of hydrating lung mucus secretions by administering uridine diphosphate (UDP) or analogues thereof and treating e.g. cystic fibrosis and chronic obstructive pulmonary disease. UDP and UTP act on purinergic receptors belonging to the P2Y family. UDP is e.g. a potent agonist of the P2Y6 receptor and UTP activates the P2Y2 receptor. However, it had recently been suggested that purinergic signalling plays a role in pathogenesis of COPD and allergic airway inflammation. P2-receptor blockade prevented the development of emphysema in smoke-exposed mice by reducing the influx into the lungs of the inflammatory cells and P2Y2 receptor-deficient mice were shown to have reduced pulmonary inflammation after acute smoke exposure (Cicko S et al., Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema, J Immunol. 2010 Jul. 1; 185(1):688-97). Similarly, blocking of the P2Y6-receptor or P2Y6-receptor deficiency reduced cardinal features of experimental asthma (Paula Vieira R et al., P2Y6 Receptor Contributes to Airway Inflammation and Remodeling in Experimental Allergic Airway Inflammation, Am J Respir Crit Care Med. 2011 Apr. 21). An activation of these receptors might thus be counterproductive and there is still a need for compounds which can be applied for the treatment of chronic obstructive pulmonary disease and cystic fibrosis.
The nucleoside uridine, which does not carry any phosphate groups, was applied before in the treatment for reduction of mitochondrial toxicity caused by highly active antiretroviral therapy (HAART) in human and was described to be safe and efficacious (Walker U A and Venhoff N, Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity, Antivir Ther. 2005; 10 Suppl 2:M117-23; EP 1365755 B1). Recently, it was also reported of uridine and its analogue 4-thiouridine in view of their protective role in acute lung inflammation. Uridine was described to suppress asthmatic airway inflammation based on an ovalbumin (OVA)-alum model and a model of house dust mite (HDM)-induced airway inflammation in mice (Müller T et al., Local administration of uridine suppresses the cardinal features of asthmatic airway inflammation, Clin Exp Allergy. 2010 October; 40(10):1552-60). 4-thiouridine was demonstrated to have anti-inflammatory effects similar to those of uridine (Evaldsson C et al., 4-thiouridine induces dose-dependent reduction of oedema, leucocyte influx and tumour necrosis factor in lung inflammation, Clin Exp Immunol. 2009 February; 155(2):330-8). Experiments were conducted using a sephadex-induced acute lung inflammation model, which shows similarity in inflammatory profile to clinical asthma.
While the use of UDP and UTP had been suggested for the treatment of COPD and cystic fibrosis, but might actually be counterproductive, the role of uridine for the treatment or prevention of chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF) were unknown until now.